Eskayef Bangladesh Limited

Introduction

Eskayef Bangladesh Limited, the world-class healthcare solution provider, is one of the leading and fastest growing pharmaceutical company of Bangladesh, which is engaged in the manufacture and marketing of a wide range of therapeutic drugs, bulk pellets and animal health and nutrition products with annual sales surpassing 60 million US dollars.

With qualified, trained and skilled professionals on its staff and its unswerving standards of quality control, the company has distinguished itself as one of the most respected names in the pharmaceutical industry. Eskayef’s manufacturing facility has transcended the frontiers after the accreditation of UK MHRA (United Kingdom Medicines and Healthcare products Regulatory Agency). The dedicated cephalosporin plant of Eskayef Bangladesh Limited is the top class state-of-the-art manufacturing facility in Bangladesh Pharmaceutical industry.

Eskayef is growing more global since 2005 and exporting bulk pellets and finished products in Asia, Africa, and Central America and also in the process of exporting in the European countries. The company is also tied up with the world leader in eye care solution Allergan Inc. Ireland.

History           

The chairman of Transcom group planted a seed of dream in 1885. As the years went by the seed began to grow and soon turned into a full-grown tree with its leaves branching out in innumerable ventures. The company which started its business in the jute and tea sectors gradually diversified its operations into:

• Health care sector
• Household electronic products
• Beverage
• Print media
• Restaurant franchise
• Software, and
• Distribution Channel

Today, TRANSCOM is one of the leading conglomerate companies of the country. The dream has turned into reality by the pragmatic vision of Mr. Latifur Rahman, the Chairman of TRANSCOM GROUP and Eskayef Bangladesh Limited and the company proudly stands symbolizing the epic tree of the seed that was planted 120 years ago.

Continuing its journey towards diversification, TRANSCOM entered the health care sector and acquired ownership of the world-renowned multinational pharmaceutical company SmithKline & French in the wake of the merger between SmithKline & French, USA and Beecham, UK in 1990. After the acquisition, the new company was styled – Eskayef Bangladesh Ltd and that has subsequently culminated under the bold and dynamic leadership of Mr. A M Faruque, the driving force and the Managing Director of Eskayef Bangladesh Limited.

Vision & mission

Eskayef envisions a leading role for itself as a catalyst for improvement of the healthcare environment.

The company’s mission is to maintain people’s health and combat disease to enhance the quality of human life so that people may live longer, healthier and more meaningful lives.

Eskayef Bangladesh Ltd. started its operation with pharmaceutical finished products for the home market. Over time we have diversified our operations into bulk products as well as animal health and nutrition products.

Finished Products

Backed by our strong technical and marketing teams we offer 149 products in 55 therapeutic segments.

Bulk product

They produce Timed Release Blended Pellets. Eskayef is the first and only pellet manufacturer in Bangladesh.

Animal health and nutrition products:

 They manufacture 28 animal health and nutrition products in 57 dosage forms and market them throughout Bangladesh.

Export
Eskayef Bangladesh Ltd. has been showing a significant outcome in exporting medicines to many countries. Eskayef Bangladesh Ltd. has started supplying medicines in 16 countries like Germany, UAE, Nepal, Bhutan, Sri Lanka, Myanmar, Vietnam, Ghana, Iraq, Indonesia, Kenya, Guatemala, Belize, Yemen, Macau and Somalia.

People

The workforce of Eskayef consists of more than 1200 to 1500 appropriately qualified, trained and skilled personnel who are drawn from different disciplines that have a bearing on the pharmaceutical industry. Our team of dedicated professionals includes a panoply of pharmacists, medical graduates, microbiologists, chemists, engineers and business management experts. Their competencies, experience and strict adherence to the work ethic go into the manufacturing and marketing of each of the company’s products.

Quality Approach

The Total Quality System is the key strength. They have inherited the Standard Operating Procedures and Quality-Approach of SmithKline & French. SK+F’s WHO audited plants produce the products conforming to the highest international standards. And to maintain the excellence that they strive to achieve, they use the most advanced technology for quality control and at each and every stage of the manufacturing process.

Why In-plant training is needed?

The term training refers to the acquisition of knowledge, skills, and competencies as a result of the teaching of vocational or practical skills and knowledge that relate to specific useful competencies. It forms the core of apprenticeships and provides the backbone of content at institutes of technology .In addition to the basic training required for a trade, occupation or profession, observers of the labor-marketrecognize today the need to continue training beyond initial qualifications: to maintain, upgrade and update skills throughout working life. People within many professions and occupations may refer to this sort of training as professional development.

On-the-job training takes place in a normal working situation, using the actual tools, equipment, documents or materials that trainees will use when fully trained. On-the-job training has a general reputation as most effective for vocational work.

Purpose of in-plant training

The purpose of in-plant training is given below-

  For the fulfillment of B.Pharm Degree.

  To achieve idea about the documentation and this is necessary for practicing GMP.

  To get ideas about the function of IPC (In Process Control) department.

  To achieve overall idea how cGMP standards are followed in a pharmaceutical industry.

  To correlate the theoretical knowledge with the practical knowledge.

  To get idea about the important machineries and equipments those are needed for the production and product analysis.

  To get ideas about the activities of QA (Quality Assurance) department.

  To get ideas about development department.

Eskayef at a glance

Company name         : Eskayef Bangladesh Limited

Company logo           :

Company slogan        : Excellence through quality

Company type           : Private limited company

Acquisition from       : SmithKline & French

Ownership                 : Transcom group

Factories                     : Mirpur (generic), Tongi (generic & cepha)

Marketing office        : Taneem Square, Banani, Dhaka.

IMS ranking              : 5th largest in Bangladesh Pharma Industry

Prime brand              : Losectil (omeprazole)

Area

Total area of Tongi Plant is 39,000 square feet (approximate) and the capacity of Warehouse 7,34,000 square feet.

Manufacturing Dosage Facilities:

• Manufacturing Unit 1
  • Tablet (Uncoated, Film Coated, Enteric Coated Tablet)
  • Capsule
  • Liquid
  • Sachet
  • Topical Preparation

• Manufacturing Unit 2 (MHRA approved)
  • Tablet (Uncoated, Film Coated, Enteric Coated Table)
  •  Capsule (Pellets)

HVAC System:

Total manufacturing area is under HVAC System.

Power Back up System:

Normally Electricity supplied from Dhaka Electric Supply Company (DESCO) & 24 hours back up power supply available through 03 Generators having capacity of 1250 KVA.

Purified Water System:

Water treatment plant have the capacity of 1000 Ltr./hr following Reverse Osmosis & UV Radiation Technology.

Current Plant Capacity:

Present production capacity in value is 120 Crore Taka & in unit packs 1.61 Crore Packs per year.

Waste Management System:

Have separate area for waste disposal under the supervision of the authorized person according to the standard operating procedure (SOP) following the direction of WHO guideline.

Effluent Treatment Plant (ETP):

Information of Tongi Plant to update the website (New Project-Cepha)

Total area of Cepha block is 45,000 square feet (approximate).

Manufacturing Dosage Facilities:

  Tablet

  Capsule

  Vial

Power Back up System:

Captive own power supply from gas generator of 2.2 MW capacity which is back up by 800 KW diesel generator.

Purified Water System:

Water treatment plant has the capacity of 1000 Ltr./hr following Reverse Osmosis Technology and the capacity of WFI 800 kg / hr.

Quality policy

Eskayef Bangladesh Ltd. is committed to ensure quality through cGMP and to ensure better life through quality medicine.

Eskayef’s quality policy

  Ensure strict compliance with WHO cGMP standards and local regulatory norms in every phase of manufacturing.

  Ensure all activities through documented SOP (Standard Operating Procedure).

  Ensure customer satisfaction by exceeding their level of expectation.

  In QC department ensure the quality through GLP (Good Laboratory Practice).

  Eskayef undertakes appropriate review, evaluations and performance measurement of its operations to ensure compliance with quality policy.

Eskayef is the other name of quality and never compromises with quality.

 Department of Eskayef

  Production department

  Product development

  QA department

  QC department

  IPC department

  Analytical Development Lab

  Microbiology lab

  MIS (Management Information System)

  Engineering & maintenance department

  Marketing department

  Finance department

  Commercial department

  Ware house

  WARE HOUSE

A warehouse management system, or WMS, is a key part of the supply chain and primarily aims to control the movement and storage of materials within a warehouse and process the associated transactions, including shipping, receiving, put away and picking. The systems also direct and optimize stock put away based on real-time information about the status of bin utilization.

Area of ware house

• Quarantine area
• Approved area
  • Active ingredient room
  • Excipient room
  • Cool room
  • Cold room
  • solvent room

Warehouse management deals with receipt, storage and movement of goods, normally finished goods, to intermediate storage locations or to final customer. In the multi-echelon model for distribution, there are levels of warehouses, starting with the Central Warehouse(s), regional warehouses serviced by the central warehouses and retail warehouses serviced by the regional warehouses and so on. The objective of warehouse management is to help in optimal cost of timely order fulfillment by managing the resources economically. Warehouse management = “Management of storage of products and services rendered on the products within the four walls of a warehouse.”

In ware house 3 types of work is done-

  Material receiving

  Storing

  Dispatch

Material stored in warehouse are-

  Raw materials (RM)

  Active

  Exipient

  Packaging material (PM)

  Finish goods (FG)

Quarantine area

Incoming raw materials are received here and waited until approved by the QA. Store in-charge is responsible for receiving the raw materials. A balance weights the raw materials.    

Conditions in the area

      Temperature:22-25⁰C

      RH:67-75%

Purpose of Quarantine area

1. To receive the material.
2. To store the material before it pass the QC test.
3. To store the material before the decision is taken whether it is passed or rejected.

Approved area

Raw materials, which bear the passed label of QC, are stored in this area.

Purpose of approved area

1. To store the approved material.
2. To store the approved materials in different condition as specified by the manufacturer.

Active room

Here only the approved active materials are stored.

      Temperature: 22-25⁰C

      RH: 67-75%

Cool room

It is important for storing raw material which are-

      Temperature and moisture sensitive.

      Volatile

Conditions:

      Temperature: 8-15⁰C

      RH: 45-60%

Penicillin and some non-penicillin actives, cooling agent and flavoring agent are stored in cool room such as Cephradine, Flucloxacillin sodium compacted, Banana flavor, Raspberry flavor, Opadry blue.

Excipient room

Only Excipients are stored.

      Temperature: 22-25⁰C

      RH: 67-75%

Name of some excipients

Sucrose, CMC, HPMC, MC, methyl paraben.

Solvent room

All the solvents necessary for formulation are stored here separately for the prevention of any accident.

Solvents: Methylene chloride, methanol, isopropyl alcohol.

Record maintained in the warehouse

Receiving record

RR No………………………….

Materials Name………………….

Batch no…………………………

Manufacturer…………………….

Supplier………………………..

Quantity………………………..

Total Quantity Record…………

Passed Label

Material……………….                                              Batch No………………………

QC Ref. no……………                                             Re-evaluation Date……………..

Analyst………………..                                              Storage Condition……………..

RR No………………..                                               Date……………………………

Identity Label

Material………………                                               AR………………………………

RR No………………..                                               Date……………………………..

Initial…………………

Bin Card

Material under test                                                      Material approved

Date…………………                                                            Date Ref-RR No…………………

Ref………………….                                                 Qty approved…………………….

Qty approved……….                                                 Qty issued……………………….

Qty rejected…………                                                            Total issued………………………

Balance……………..                                                 Balance…………………………..

Color of labels

Sampled: Yellow                    Rejected: Red

Passed: Green                         Identity test: Blue (Only for active ingredients)

Processing of raw materials

• At first raw materials come into the quarantine area. RM store in-charge make a receiving record. One copy of RR is sent to the QC for sampling the RM.

• Raw materials are sampled by QC from quarantine area within 4 days after receiving the RMs. Every container of actives are is sampled for testing but Excipients are randomly sampled by square root of n+1.

• If the sampled materials passed the QC test they are given passed label and transferred to the approved area within 10 days after giving passed.

• After approving, actives and excipients are stored in active store room, Excipient store room, solvents are in the solvent room.

Quality assurance

Quality assurance

Quality assurance, or QA for short, is the systematic monitoring and evaluation of the various aspects of a project, service or facility to maximize the probability that minimum standards of quality are being attained by the production process. QA cannot absolutely guarantee the production of quality products.

Quality assurance is a vital department in any pharmaceutical company since it is involved in assuring quality of product from product development, dispensing, production, packaging up to release of finish goods. For benefit of the patients SK+F Bangladesh Ltd. gives priority to production of quality product. They believe that only quality product can satisfy the consumer and a satisfied customer is a great advertiser for the company. For this reason they have taken a strict and inflexible process to check the product for any kind of defects or lack of quality. For quality control SK+F Bangladesh Ltd. procures quality raw materials from their approved source.

They ensures quality by following 10 important point of cGMP as follows-

1. We must have written procedures.
2. We have to follow our written procedures.
3. We have to document our work.
4. We have to validate our work.
5. We must design and build proper facilities.
6. We have to maintain our facilities and equipment in proper state.
7. We must have the education, training and experience to perform job.
8. We have to maintain a clean environment.
9. We must control our quality.
10. We have to periodically audit for compliance

Responsibilities of QA

1. Raw material analysis

      Source development

      Commercial consignment

      Re-testing

      Keeping sample & relevant documentation.

1. Packaging material analysis

      Source development

      Commercial consignment

      Finish product analysis

      In process control

      Bulk product

1. Finish product analysis

      In process quality control

      Bulk product analysis.

1. Packed product analysis
2. Water analysis
3. Calibration
4. Stability study
5. Product monitoring
6. Validation
7. Environmental monitoring
8. Documentation

Quality assurance department

1. QC

      Chemical test (Solubility, pH, Impurity)

      Microbiological test (Microbiological limit test, antibiotic test)

1. IPC (Physical test)

    Quality control

Quality control is the part of GMP which is concerned with sampling specification and tasting and with organization documentation and release procedures which ensures that the necessary and relevant tests are carried out and that materials are not released for sale or supply until this quality has been judge to be satisfactory. In SK+F Bangladesh Ltd. quality control is done very very strictly as their moto is “Excellence Through Quality”.

Eskayef’s quality control department has its own GLP. GLP guidelines are as follows-

• Cleanliness
• Safety precaution
• Sampling and testing
• Documentation
• Equipment
• Reagent
• Packaging
• New product

Every segment of QC department plays the similar role in quality testing. They strictly follow the CofA (Certificate of Analysis) for quality testing, and unless and until the sample meets all the requirements to pass being within moderate range, they are not passed.

Activities of the Quality Control Department

1. Method development for analysis.
2. Receiving of the samples to be tested from QA department
3. Giving RR (receiving record) number
4. Issuing release, rejecter quarantine advice for each batch of raw material and final product.
5. Performing all tests procedure for incoming samples according to the schedule
6. Maintaining quality control tests records with the signature of the person who perform the tests.
7. Performing environmental monitoring test.
8. Calibrations and standardization of equipments.
9. Ensuring precision and accuracy of all testing methods
10. Control of all laboratory reagents
11. Research and development of any new method & its validation
12. Testing of any return goods\
13. Stability test for finish products
14. Before purchasing of raw materials, testing of all BP & USP specifications of the sample sent by the seller
15. QC department plays the central role in case of the complaints and recall of marketed products
16. Water testing.

Tests done by the QC department

1. Raw materials

• Physical test

      Appearance

      Identity

      IR

      Melting point

      HPLC

      Clarity of solution

      Color of solution

      pH

      Specific gravity

      Viscosity

      Turbidity

      Bulk density & tapped density

      Mesh size

      Total impurities

      Metal content

      Related substances analysis (HPLC)

      Residue on ignition (AAS)

• Chemical test

      Potency

      Assay

      Loss on drying (LOD) or moisture content test (KF)

1. B.     Finish products:

Solid

• Physical test

      Dissolution test

      Disintegration test

      Uniformity test

      Average weight

      Thickness

      Friability

• Chemical test

      Potency

1. C.    Dry granulation powder

• Physical test

      Appearance of dry granules

      Water content

      Reconstitution time

      Sieve test

Test for product

Tablet

      Appearance

      Hardness

      DT time

      Moisture content

      Potency determination

      Stability

Capsule

      Appearance

      DT time

      Moisture content

      Assay

      Dissolution

Liquid

      Appearance

      Specific gravity

      Viscosity

      Microbiological assay

Test for packaging material

Aluminium foil, PVC & PVDC

      Printing & design

      Color

      Width

      Length

      Thickness

      Weight

      Perforation test

Plastic cap                          

      Weight

      Diameter

      Appearance

      Volume capacity

Carton

      Appearance

      Weight

      Moisture content

Instruments used in SK+F’s QC lab

• Ø HPLC (Identification and potency determination)

• Gas chromatography (Identification and potency determination)
• Centrifugator (For centrifugation)
• Tapped density measuring meter
• Melting point measuring meter (To determine the melting point)
• Polarimeter (To determine optical rotation)
• Balance (For measuring weight)

• Ø UV spectrophotometer (Identification and potency determination)

• pH meter (To determine the pH of the solution)
• Refractometer (To determine the refractive index)
• Sonicator (To dissolve the solute & removal of bubble from solution)

• Ø Dissolution test apparatus

• Ø Atomic absorption spectrophotometer

• Ø Infra Red spectrophotometer

• Ø Refrigerator

In process control (IPC)

IPC tests are designed to ensure that the process is under control throughout the manufacturing to ensure quality at every stage to make a successful batch at the first attempt.

The full benefits of IPC come from getting the things “Right the first time”.

Advantages of IPC

      Allows timely action

      Improves productivity

      Reduces rejection cost

      Reduces batch testing at the end

      Reduces the chances of batch failure

Function of IPC

1. In process control maintenance
2. Solve minor problems of production or packaging
3. Assessment of the intermediate products & bulk products for further processing
4. Physical testing
   1. Hardness of tablets
   2. Thickness of tablets
   3. Friability of tablets
   4. Disintegration time of tablets
   5. Diameter of tablets
   6. Size and shape of tablets & capsules
   7. Weight variation
   8. Appearance
   9. pH of liquids
   10. Viscosity of liquids
   11. Specific gravity
   12. Chemical testing

Moisture content

1.                                I.            KF (Karl Fiesher)
2.                             II.            LOD (Loss on drying)
3. Stability testing

Microbiology Lab

Microbe such as mold bacteria, viruses etc. can freely exist in an uncontrolled environment. Microbiology section will just determine the microbial contamination monitoring. Microbiology is the study of microorganism. It is concerned with their form, structure, reproduction, physiology, metabolism and classification

The microbiology department in SK+F Bangladesh Ltd. is well equipped and various tests are performed here.

Microbiological assay and other test

The department of microbiology performs the role of immense importance to follow the GMP and to formulate as well as to implement the SOPs.

The overall activity profile of the microbiological section of QC department of SK+F  can be presented briefly in the following ways-

• Microbial count– Water, raw materials, finished products, packing container.
• Environmental study– All manufacturing & filling areas including aseptic filling room.
• Validation– Steam and dry heat sterilizes, oven, cleaned equipments.
• Personal hygiene test– All production area.

Media used in microbiology lab:

1. 1.      Syabean casein digest medium
2. 2.      Nutrient broth
3. 3.      Nutrient agar
4. 4.      Nutrient gelatin
5. 5.      Eosin Methylene blue agar
6. 6.      Fluid lactose

Equipments of microbiology lab

1. Autoclave

1. Laminar air flow station
2. Colony counter
3. Microscope
4. Mixing unit
5. Incubator

Procedure of limit test

 0.85% NaCl (Saline water)

 9 ml in a test tube + 1 ml sample

Vortex for uniform mixing

0.1  ml in petridish and spreading

Incubation in incubator for 49-72 hrs

Limit: 1000CFU/ml

Calculation for limit test

Solid = No of colonies/plate X dilution factor / sample wt. / vol. / of sample

Liquid= No of colonies/plate X dilution factor / Sample wt

 Product development

Product development department is very important dept. in pharmaceutical industry. It deals with development of new drugs and new dosage forms of existing product. This dept. of the pharmaceuticals is stimulating and challenging and is suited specially to pharmacist with strong scientific background.

Functions

• New drug specification
• Experimental batch production (EB)
• Pilot batch production (PB)
• Formulation studies
• Verification of drug compatibility with the formulation Excipients
• Perform extensive stability study on the finished product
• Scale up from laboratory to commercial batch of the products
• Optimization of production process & concurrent process validation
• Development of the most suitable analytical methods to evaluate the finished products and concurrently validate the method
• Preparation of master documents for both manufacturing and analysis
• Studies to determine the best packaging for storage
• To formulate new product
• To enhance the quality of the existing product by bringing changes in formulation
• To perform research studies.

Pre-formulation study

Pre-formulation study is the study of the chemical and physical properties of the drug components prior to the compounding process of formulation. The purpose of the study is to understand the nature and characteristics of each component and to optimize conditions of dosage form manufacture.

Stages of pre-formulation study

      Physiochemical properties and analytical testing for drugs

      Data supporting the development of dosage forms

      Support for quality control and finished product manufacturing.

Production department

1. Manufacturing unit 1
   1. Solid section
   2. Liquid section

• Liquid 1
• Liquid 2
• Liquid 3 (Classified)

1. Semi-solid
2. Packing Hall
3. Manufacturing unit 2 (UK MHRA approved)
4. Liquid sterile
5. Cepha production.

Solid section

• Tablet
• Capsule
• Dry syrup
• pellets

Tablets

Tablets are solid dosage form with or without coating which are prepared by compression. Excipient may include diluents, binders, disintegrating agent, lubricant, sweetening agent, flavoring agent and coloring agent. Tablets contain a single dose of one or more active ingredients and obtained by compression of uniform volume of particle. They are intended for oral administration. SK+F has conventional, sustained release, coated(sugar, film), and chewable tablet preparations.

Production area

1. Dispensing room
2. Granulation room
3. Blending room
4. Compression room
5. Encapsulation room
6. Coating room
7. In process control section
8. Wash bay.

Dispensing

From the warehouse at first all the raw materials are bought into the dispensing room where the required amount of material is weighted.  Dispensing is the first step of manufacturing. Dispensing of raw material is done in the dispensing boot under laminar airflow. At first all excipients are dispensed and then the active ingredients are dispensed.

Process of dispensing

1. Requisition is given to warehouse for raw materials prior to granulation
2. Raw materials are collected from warehouse and transferred to a clean dispensing room.
3. Dispensing condition should be maintained
4. Weighing of raw materials should be according to MO (manufacturing order)
5. Checking of quantity dispensed
6. Excess material returned to warehouse.

Dispensing Bulk Room

After dispensing and before manufacturing all the raw materials are kept in the dispensing bulk room and all necessary data are recorded.

Granulation

Most powders cannot be compressed directly into tablets because-

• The lack the proper characteristics of binding or bonding together into a compact entity and
• They do not ordinarily possess the lubricating and disintegrating properties required for tableting.

Reason of granulation

1. To prevent segregation of the constituents in the powder mix
2. To improve flow properties of the mix
3. To improve compression characteristic of the mix
4. The granulation of toxic materials will reduce dust generation
5. Granules are denser and thus occupy less volume per unit weight.

Granulation is of two types

1. Wet granulation
2. Dry granulation

Wet granulation:

Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis.

Following are the steps of wet granulations:

1. Step 1: The active ingredient and excipients are weighed and mixed.
2. Step 2: The wet granulate is prepared by adding the liquid binder–adhesive to the powder
3. Blend and mixing thoroughly. Examples of binders/adhesives include aqueous preparations of cornstarch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, gelatin, and povidone.
4. Step 3: Screening the damp mass through a mesh to form pellets or granules.
5. Step 4: Drying the granulation. A conventional tray-dryer or fluid-bed dryer are most commonly used.
6. Step 5: After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to create granules of uniform size.

Advantage of weight granulation

• Improve flow properties
• Densification
• Improved compression characteristics
• Reduction in dust
• Prevention of segregation of powder mix

Disadvantage of weight granulation

• Stability may be a concern for moisture sensitive drug
• Time, space and equipment required are costly

Dry granulation

Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced.

Flow chart of dry granulation

• Raw material weighing
• Sieving through vibratory shifter
• Dry mixing in double cone blender
• Slugging
• Milling
• Sieving
• Final mixing (Lubrication)
• Compression

Advantage of dry granulation

• One step process
• Time saving
• Moisture sensitive drugs can be granulated

Disadvantage of dry granulation

• Decreased compression characteristics
• Excess dusting

Blending

Purpose of blending

To lubricate the granules and powder mix for easy ejection during compression and to render the tablet surface polish and smooth.

Compression

It is the final step of tableting. After compression, tablets are ejected from punch.

Tableting cycle is as follows-

1. Hopper: contains the granulated material
2. Feed frame: Fed by the hopper to hold the granules as it is fed into the die
3. Feed paddles: ensures that the granule is keep agitated to correct filling of the die bore
4. Compression station: where full compression of the tablet is achived
5. Ejection station: this the station where the tablet leaves the die for take-off.

Problem during tablet compression

• Capping & Lamination

Cause:

      Use of too dry granules in compression

      If compression pressure is too high

Remedy:

      By altering the pressure adjustment

      By using proper granules and required amount of fine particles

• Picking and sticking

Cause:

      For using wet granulation during compression

      Excessive moisture content of the granules.

Remedy

      By using dry granules and by adding a lubricant to the granules

      By replacing the worn dies and punches.

• Hardness variation

Cause:

      Space between upper & lower punches at the time of compression

      Inappropriate pressure applied in the upper punches

Remedy

      The defect can be overcome by solving the causative effects.

Coating

Temperature and humidity must be controlled during coating process.

Coating types depend upon

      Tablet surface

      Tablet shape

      Nature of active ingredient

Types of coating

1. Sugar coating

Purpose of sugar coating

      Protection from sun, moisture and environment

      To mask bitter taste & odor to increase the aesthetic value

      Prevent dusting

1. Film coating

Purpose of film coating

      Masking of taste, odor and appearance

      Can act as a barrier over the surface of the tablet

      Enteric coating

      Can modify the release of the drug

Reasons of enteric coating

      Modification of drug release

      Repeat action and give sustained release pattern

      Stop gastric irritation

Capsule

Capsule is a solid dosage form, in which medicine are enclosed in hard or soft capsule shell, made from gelatin. Generally SK+F use empty hard gelatin shell.

Steps of encapsulation

1. Sieving of raw material (active & excipients)
2. Mixing (Double cone blender)
3. Compaction (If required) if bulk material is micronized or normal grain
4. Encapsulation
5. Polishing
6. Blister/ foil pack

Encapsulation process

1. Empty shell are taken in empty shell hopper
2. Empty shells are transferred from hopper to die holder
3. Body and cap are separated by vacuum pump
4. Pellets/ ingredients are incorporated into the body
5. Sealer seal the body and cap
6. Ejection

Pellets

Pellets are the dosage form mostly defined as the circular granule like beads where the drug is coated on to the surface of the NPS (Non-peril-seeds) made using sugar, lactose and maize starch.

SK+F usually markets combined drug therapy in pellets form. The combination drugs are-

1. Feofol=FeSO₄  + Folic acid
2. Feofol CI=FeSO₄ + Folic acid + Carbonyl iron
3. Zeofol=Zinc + FeSO₄ + Folic acid
4. Folvit CI=FeSO₄ + Folic acid + Ascorbic acid + Vit-B Complex + CI
5. Zilvit=Zinc + Folic acid +Ascorbic acid + Vit-B complex +CI

Advantage of pellets

• For modify release
• Increase surface area
• Decrease dose dumping
• Decrease chances of toxicity
• Decrease drug interaction
• Easy of manufacturing

Liquid section

The main purpose for manufacturing oral liquid dosage form is to serve the child patients and patients having fear and problems with swallowing solid dosage form.

Steps involved in liquid preparation

1. Dispensing
2. Addition of preservative and dissolve properly
3. Then the total amount of sucrose is added
4. Maintain the temp. in between 80⁰-90⁰C for mixing
5. The total preparation is transferred to another vessel
6. Filled into bottles and sealed

Bottle washing

Bottle used for liquid preparation are washed in following step

      Bottles are taken to the machine

      Washed using potable water both inside and outside

      Then washed using purified water

      Compressed air

      Bottles are dried in the oven at 180⁰C (In case of dry syrup)

Steps involved in liquid filling

•       Liquid taken into the filling vessel
•       Automatic filling
•       Cap sealing
•       Label printing

Packaging

Packaging is the process by which the pharmaceutical products are suitable packed in such way that they should retain their therapeutic effectiveness from the time of their packaging to consume by the consumers.

SK+F has a well established packaging department.

There are two types of packaging

1. Primary packaging. (Direct contact with the product e.g. PVC)
2. Secondary packaging. (No contact with the product e.g. Carton)

Material used in packing section

•       Aluminium foil
•       PVC film
•       PVDC film
•       Bottle
•       Pilfer proof cap
•       Label
•       Unit carton
•       Insert
•       Plastic spoon
•       Plastic dropper
•       Plastic cap
•       Stopper
•       Shipping carton

Flow chart for PVC /PVDC blistering

• PVC /PVDC are placed on roller
•  Pocket formation by pressure (6-8 bar)
•  Tablet / capsule feeding
• Sealing and batch printing
• Perforation
• Cutting

 Manufacturing Unit 1

The rooms containing the machines/instruments are listed below:

 Topical Area

Manufacturing Unit 1 contains Topical Area where 15 topical products like creams, ointments and some liquid preparations (disinfectants) are manufactured. The names of the machines which are available in this area is listed below:

Manufacturing Unit 2

The manufacturing unit-2 of Eskayef is located in the ground floor of the generic block. The whole area of this unit is GMP controlled and is approved by both UK MHRA and TGA. Here standard operating procedure (SOP) is strictly followed. In this unit solid dosage form like tablets, capsules and particularly pellets (with and without active material) are manufactured. Here, the entry and change room for officer and operator is different. There are pressure gauges infront of every door of this unit to measure the pressure difference. The corridor of this unit has negative pressure (5-10 pascal) than the rooms where manufacturing operations (10-30 pascal) are carried out. The names, purpose of rooms and instruments in this unit are given below.

Wash Bay 1 and 2

In this room cleaning tools and reagents are stored. It also contains record/log book for cleaning, portable water (hot/normal) line etc. For cleaning the floor different reagents are used in every alternate week. Reagents that are used for cleaning the floor are Welon, Detol, Jet, Vim, and IPA. These are used to clean product non contact surfaces. No reagents are used to clean the product contact surfaces. According to GMP, for cleaning the product contact surfaces generally at first, flow of portable water, second, flow of hot portable water and third, flow of purified water is used. Washing bay-1 contains a washing machine for cleaning the garments.

Sieving Room

In this room sieving operation is performed by using vibratory siefter. For instance, sugar can be sieved to get the different sizes that are required in manufacturing process.  

Oven Room

In this room pellets and powder are dried. The pellets which are dried can be NPS (non peril seed)/dummy or active. This room contains an oven named Indo-German Oven which is steam heated oven. It contains 28 trays and the maximum temperature that can be raised is 100°C.

Dispensing Room

From the warehouse at first all the raw materials are bought into the dispensing room where the required amount of material is weighted.  Dispensing is the first step of manufacturing. Dispensing of raw material is done in the dispensing boot under laminar airflow. At first all excipients are dispensed and then the active ingredients are dispensed. This room also contains 3 weighing balances.

Dispensing Bulk Room

After dispensing and before manufacturing all the raw materials are kept in the dispensing bulk room and all necessary data are recorded.

Intermediate Bulk Store (IBS) 1 and 2

After encapsulation of the capsules and before packaging/after formation of the pellets/after formation of the granules of tablets and before compression all the materials are kept in this room in a double polyline  packs.

Extruder and Spheronizer Room

In this room NPS are prepared. It contains two instruments, extruder and spheronizer. Extruder is used to produce extrusion during pellet manufacturing. Spheronizer is used to make the formed extrusion spherical and hence formed the final pellets which are then dried in the oven. The specification of the two machines is as follows:

 Granulation room contains the following instruments:

 Coating Room

This room contains another coating machine which is more sophisticated than GC Coater. This coating machine is programmable and the software related problems are solved by the manufacturer of the machine. The manufacturer of this machine is Nicomac Coating System- ELT450NCS102 (Italy). It has 4 spray guns with 1-12 rpm and the capacity is 450 kg.

Blending Room-1 and 2

Blending operation is performed in these rooms. If the amount is less than 300kg then room-1 is used and if the amount is more than 300 kg than room-2 is used.

Tablet Compression Room

Granules are compressed into tablet in this room. This room contains Rotary Tablet Press Machine (MRC-37D) with metal detector and dedustor which is made by Sejong Corp. (Korea). It has 37 stations and the maximum capacity is 250000 tablets per hour.

Conventional Coating Room

In this room active material is coated in the NPS by using two conventional coating machines made by Manesty (UK). Each pan contains one spray gun and the capacity of the machine is 60-90 kg.

Liquid Sterile Block

In this unit three problems are generally encountered and are analyzed. These are:

1. Critical Problem

2. Major Problem

3. Minor Problem

There are 12 products are manufactured in this unit. These are:

1. Ketonic-60

2. Ketonic-30

3. Peptilaze

4. Zofra

5. Fibrino

6. 10 ml WFI

7. 5 ml WFI

8. Lidocane 2ml

9. Lidocane 4ml

10. Solbion

11. Volmex

12.Timothi

Ampoules filling and sealing room

Ampoules are filled and sealed under class ‘A’ environment. The machine used for filling and sealing operation is called Rota ampoule Filling Machine (Germany) which has 6 nozzles. It should be noted that there are two types of ampoules: open mouth and closed mouth. Closed mouth ampoules do not require any washing.

The Steps of Ampoule Filling and Sealing is shown in the below chart:

Deboxing

Washing

 Depyrogenation (290°C, 10 minutes)

Filling

Sealing

The useful machines for this purpose are:

1. Depyrogenation Machine: This machine is manufactured by East China Pharmaceutical Machinery Co. Ltd. (China). By using this machine the ampoules are depyrogenated by heating at 290°C for 10 minutes.

2.  Partical Counter Machine: This machine is manufactured by Lasair III 5100 (USA).

3. Filling and Sealing Machine: Rota ampoule Filling Machine. This machine is manufactured by Bausch (Germany).

Production (Cepha Block)

In Eskayef, manufacturing plant of cephalosporin is completely isolated from the other working area of the plant to prevent the contamination and cross-contamination and the development of resistance. The following table contains the names of the instruments and machines that are used by the production department of Cepha Block:

 Documentation

Eskayef Bangladesh Ltd. records all the necessary information and documents in order to ensure the availability of all data required for manufacture, packaging and quality control and record the history of a batch.

RM (Raw material)

      Raw material suppliers CofA

      RM sampling register

      RM register book

      RM CofA

PM (Packaging material)

      PM sampling register

      PM register

      PM CofA

      PM’s specification

      Files for PM’s standard

QC Lab

      Product control direction according to USP & BP

      In-process register

      Product CofA

      Product trend card

IPC

      Technical information test

      LOD, pH and specific gravity\

      In-process sheet

      Wt. variation, friability, hardness, DT.

Production

      Manufacturing order (MO)

      Batch manufacturing record (BMR)

      Batch packaging record (BPR)

      Finish order (FO)

      Standard operating procedure (SOP)

Validation

a)    Process validation (Done in every 3-5 batches)

      Prospective validation

      Rate respective validation

      Concurrent validation

       Re-validation

b)    Equipment validation

      DQ=  Design qualification

      IQ= Installation qualification

      OQ= operating qualification

      PQ= performance qualification

Management Information System

Management may be defined as the process of planning & maintaining an organization to achieve goal.

Function:

• Planning: it involves selecting objectives & function to achieve goal
• Organizing: To organize skilled persons & assigned activities to them so that the activities can be carried out properly
• Staffing: It involves proper selection, placement, training and development of personnel
• Leading: It includes planning, controlling and implement by leader

Engineering department

The engineering department of SK+F is well organized and fully equipped. The main focus of this department is to supply and maintain the utilities of the factory such as water supply, electricity supply, wiring & AC system. Another important focus of this department is maintenance of the machineries.

Function

      Water treatment plant management & maintenance

      Compressed air

      Gas supply

      Air conditioning system

      Power supply & management

      Boiler

      HVAC system

      Installation of machine

      Maintenance and trouble shooting of machines

      Technical support.

Compressed air

The compressed air supply system is called the pneumatic drive. It is used to produce compressed air. The air compressor is Atlas Copco (Belgium). Capacity: 6-8 bar (max 10 bar)

Compressed air used in-

      Coating purpose

      Bottle washing

      Blister pocket forming

Water treatment plant

      To produce WFI

      To produce PW

SK+F has two types of water treatment plant

1. Stil mas (Italy)
2. Doshion plant (india)

Power substation

It is a very vital point of the whole engineering system which deals with the electricity system of the entire plant area. It involves the function of generators.

Boiler

The boiler is the most important and vital sector the engineering department. It is also very dangerous because of the use of steam of very high temp. and pressure.

Steam used in-

      Liquid compounding

      Sterilization

      Humidity control

      Sanitization

In SK+F, the boiler is Hurst boiler (USA).

ETP (Effluent treatment plant)

Used to remove organic material from water

4 types of chemical are used such as

      CaCO₃ (for pH control)

      Fitkiri (Flocculants)

      Polymer (Coagulant)

      DAP & urea (Non-aerobic decomposition)

Capacity: 50000l/day

Discharge water pH: 7-9

HVAC system

Total manufacturing area of SK+F is under HVAC system. It is used –

      To prevent cross-contamination

      Temperature control

      Particle count control

      Pressure control

Particle count in different zone

 Conclusion

Eskayef is the name of quality. The slogan of SK+F is “EXCELLENCE THROUGH QUALITY”All the staff of this company believes and follow the sentences “practice GMP and make GMP practice & quality through GMP”

It is really an example of ideal company in all respects in our country. The qualities of all are very fine products in comparison with other products of market as “quality is the measure of excellence”. By using the modern developed instrument & technology and all time observing the manufacturing instructions, SK+F is giving the most quality product to the markets. For this reason both patient and physician easily prefer the products of Eskayef.

Management system of this company is dynamic and documentation systems excellent. During our training period, we divided into two groups to strengthen the knowledge about very section. It has some good impact on the training but 3 weeks are not enough to know everything about training.

After completing my training with my limited knowledge would like to point out some suggestion about different departments of SK+F for the kind consideration of the authority.

Although, there are some limitations SK+F is the company that never compromises with quality. So, I feel myself lucky to complete my in-plant training in this company.

I wish Eskayef Pharma would develop day by day and achieve its goal.